Triptonide enhances DNA damage by inhibiting TRIP13‑mediated DNA repair and synergizes with bortezomib to suppress multiple myeloma.

چکیده اصلی

Multiple myeloma (MM) is a malignant disorder of plasma cells. Combinations of bortezomib (BTZ) with other therapeutic agents remain the mainstay of MM treatment. However, the rising incidence of drug resistance among patients with MM underscores an urgent need for novel therapeutic strategies. The present study identified triptonide (TN), a small‑molecule monomer extracted from the traditional Chinese herb Tripterygium wilfordii Hook. f., as a synergistic agent that enhanced the anti‑MM activity of BTZ, following a screening of 198 compounds from a ubiquitination‑focused library. TN effectively inhibited cell proliferation, induced apoptosis, and reduced cell viability in MM cells. Furthermore, the synergistic anti‑MM effect between TN and BTZ was validated across MM cell lines, primary MM cells, and xenograft mouse models of MM. Mechanistic investigations revealed that TN synergizes with BTZ by enhancing DNA damage through the suppression of TRIP13‑mediated DNA repair pathways, including non‑homologous end joining and homologous recombination. Notably, TRIP13 knockdown attenuated TN‑induced DNA damage and apoptosis, and diminished the synergistic effect of TN and BTZ on MM cells. Collectively, TN represents a novel anti‑MM agent, and the combination of TN with BTZ constitutes a promising therapeutic strategy for the treatment of MM.

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